https://phaidra.vetmeduni.ac.at/o:5455 Somatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases Grün, Sarah Sarah Grün Rensing-Ehl, Anne Anne Rensing-Ehl Suske, Tobias Tobias Suske University of Veterinary Medicine Vienna Wolter-Mess, Julian Julian Wolter-Mess Gehrig, Jonathan Jonathan Gehrig Mann, Jasmin Jasmin Mann König, Christoph Christoph König Hauri, Mathias Mathias Hauri Heeg, Maximilian Maximilian Heeg Leahy, Timothy Ronan Timothy Ronan Leahy Genevieve, David David Genevieve Gaillard, Jean-Baptiste Jean-Baptiste Gaillard Broly, Martin Martin Broly Bourdin, Arnaud Arnaud Bourdin Castro, Carla Carla Castro Seidel, Lea Lea Seidel Bengsch, Bertram Bertram Bengsch Aichele, Peter Peter Aichele Weißert, Kristoffer Kristoffer Weißert Fernandez-Orth, Juncal Juncal Fernandez-Orth Schipperges, Vincent Vincent Schipperges Andrieux, Geoffroy Geoffroy Andrieux Boerries, Melanie Melanie Boerries Cabezas-Wallscheid, Nina Nina Cabezas-Wallscheid Erlacher, Miriam Miriam Erlacher Elling, Roland Roland Elling Speckmann, Carsten Carsten Speckmann Heller, Lara Lara Heller Schulte, Björn Björn Schulte Lorenz, Myriam Myriam Lorenz Schwarz, Klaus Klaus Schwarz Moriggl, Richard Richard Moriggl Ehl, Stephan Stephan Ehl 0000-0002-9265-2721 Elsevier journal article open access eng Background Inborn errors of immunity are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking inborn errors of immunity. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5BN642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined. Objective We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes. Methods We investigated 3 new patients—including one adult—with STAT5BN642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes. Results Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2–mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients. Conclusion A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease. STAT5B somatic mosaicism hematopoietic stem cells clonal hematopoiesis immune dysregulation T-cell lymphoproliferation autoimmunity atopy mTOR inhibition http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:5455/download 10.1016/j.jaci.2025.12.993 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Journal of Allergy and Clinical Immunology issn:0091-6749 VoR Journal of Allergy and Clinical Immunology 157 4 2.61 MB 2026